8-98427986-G-C

Position:

• chr8-98427986-G-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_020697.4(KCNS2):​c.7G>C​(p.Gly3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000202 in 1,388,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: KCNS2 NM_020697.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.52

Genes affected

KCNS2 (HGNC:6301): (potassium voltage-gated channel modifier subfamily S member 2) Predicted to enable voltage-gated potassium channel activity. Predicted to be involved in potassium ion transmembrane transport and regulation of delayed rectifier potassium channel activity. Predicted to be located in perinuclear region of cytoplasm and plasma membrane. Predicted to be part of voltage-gated potassium channel complex. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

STK3 (HGNC:11406): (serine/threonine kinase 3) This gene encodes a serine/threonine protein kinase activated by proapoptotic molecules indicating the encoded protein functions as a growth suppressor. Cleavage of the protein product by caspase removes the inhibitory C-terminal portion. The N-terminal portion is transported to the nucleus where it homodimerizes to form the active kinase which promotes the condensation of chromatin during apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

STK3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0516918).
• BP6: Variant 8-98427986-G-C is Benign according to our data. Variant chr8-98427986-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3287748.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNS2	NM_020697.4	c.7G>C	p.Gly3Arg	missense_variant	2/2	ENST00000287042.5	NP_065748.1
STK3	XM_047422133.1	c.1423+9117C>G		intron_variant			XP_047278089.1
STK3	XR_007060752.1	n.1571+9117C>G		intron_variant
STK3	XR_007060753.1	n.1571+9117C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNS2	ENST00000287042.5	c.7G>C	p.Gly3Arg	missense_variant	2/2	1	NM_020697.4	ENSP00000287042.4
KCNS2	ENST00000521839.1	c.7G>C	p.Gly3Arg	missense_variant	2/2	5		ENSP00000430712.1
STK3	ENST00000517832.1	n.483+6141C>G		intron_variant		3
STK3	ENST00000649151.1	n.427+6141C>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000180 AC: 3 AN: 167034 Hom.: 0 AF XY: 0.0000223 AC XY: 2 AN XY: 89536

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000398

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000453

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000144

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000202 AC: 28 AN: 1388614 Hom.: 0 Cov.: 31 AF XY: 0.0000205 AC XY: 14 AN XY: 682068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000849

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000511

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000177

Gnomad4 OTH exome AF: 0.0000350

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000169 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 01, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.86
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.052	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.27
Sift	Benign	0.98	T;T
Sift4G	Uncertain	0.036	D;D
Polyphen		0.0	B;B
Vest4		0.077
MutPred		0.19		Gain of MoRF binding (P = 0.079);Gain of MoRF binding (P = 0.079);
MVP		0.41
MPC		0.70
ClinPred		0.051	T
GERP RS		1.2
Varity_R		0.073
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs766499929; hg19: chr8-99440214;